Hepatitis B in Latin America: epidemiological patterns and eradication surgery

Hepatitis B !n Latin America: epldemlologlcal patterns and eradication strategy O.H. Fay and the Latin American Regional Study Group* A comprehensive epidemiological analysis of hepatitis B virus (HBV) endemicity and transmission in Latin America was carried out to suggest policies and strategies for the use of hepatitis B vaccine in the region. The pattern of HBV endemicity based on available data from blood bank screening programmes and clinical and epidemiological studies varied widely: it was low in temperate South America, Mexico and some Caribbean islands; moderate in Brazil, Andena countries, part of central America and the Caribbean; and high in Hispaniola, St. Kitts]Nevis and in the Amazon basin (parts of Brazil, Peru, Venezuela, Colombia). Statistical estimates of HB V-related morbidity showed that >150000 acute H B V cases occur per year. As the endemicity of HBV varies considerably, different prevention strategies should be applied in this area. The highest priority should be the prevention of perinatal and early childhood transmission, but vaccination of adults belonging to high-risk groups should also be recommended. Keywords:Hepatitis B; Latin America; epidemiology; endemicity; delta virus

Introduction Hepatitis B virus (HBV) infection is a disease of the utmost public health importance for Latin America. Infection with this virus causes significant morbidity and mortality, resulting in acute hepatitis and giving rise to chronic hepatitis, cirrhosis and primary hepatocellular carcinoma (PHC) - consequences of persistent viral infection. With the advent of highly effective vaccines to prevent HBV infection and the expected decrease in vaccine cost in the coming years, it has become feasible and mandatory to begin planning large-scale HBV vaccination programmes. To this end and to establish priorities and policies for the allocation of limited resources to prevent this disease, a comprehensive epidemiological study was conducted to produce a clearer picture of the patterns of HBV endemicity and transmission in Mexico, the Caribbean, Central and South America.

Evaluation of the extent of hepatitis B infection in Latin America The information was compiled and synthesized from data published in W H O statistical reports 1, international, national and local journals, as well as from material provided by government health ministeries, blood banks, Centro de Tecnologia en Salud Publica, Facultad de Ciencias Bioquimicas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina. *Members of the Latin American Regional Study Group are: Drs L.C. da Costa Gayotto (Brazil), J.C.F. da Fonseca (Brazil), R.K. Fernandez Barboza (Venezuela), B. Hull (Trinidad), D. Kershenobich (Mexico), F. Pinheiro (PAHO), H. Tanno (Argentina) and O.H. Fay (Chairman) 0264-410X/90/S 10100-07 © 1990 Butterworth & Co. (Publishers) Ltd

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scientific societies and professional medical associations in the region. Medline-referenced journal articles were reviewed. Only those articles presenting suitable methodologies and selection criteria were considered. Additional sources of recent data were the contributions of participants at three meetings (Rio de Janeiro, 1985; Caracas, 1986; Medellin, 1988) of the Advisory Group on Viral Hepatitis, established by the Pan American Health Organization (PAHO). Individual researchers contacted in various countries also provided valuable unpublished data and personal communications. The prevalence of HBV infection was based on assays of blood specimens for hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) or to hepatitis B core antigen (anti-HBc). Earlier reports often made use of reverse haemagglutination, latex and/or counterimmunoelectrophoresis tests, although radioimmunoassay and enzymeimmunoassays have been increasingly used in recent years. Results of testing for hepatitis B e antigen (HBeAg), antibodies to HBeAg (anti-HBe), and hepatitis 6 virus (HDV) are presented when available and appropriate. It should be noted that blood bank data constitute a chief source of information regarding HBV endemicity in this area. As such, the accuracy and utility of such statistical data for calculating HBV prevalence rates has inherent limitations since the blood donor population is usually > 18 years of age; blood donors constitute a selected sample in which the sick are not included; usually only those blood banks located in urban areas are equipped to perform HBV serological testing; and important differences in testing methodology exist. In addition, quality control is limited in scope and both sensitivity and specificity may be low. Nevertheless, the consistent epidemiological patterns which emerge, corroborated by numerous local and regional studies,

HBV eradication strategy in Latin America: O.H. Fay et al.

can be used to formulate and implement effective strategies for the control and eradication of HBV infection based on the use of hepatitis B vaccines. Estimates of HBV-related morbidity and morality were based on a combined approach 2 utilizing direct (disease reporting and epidemiological studies) and indirect methods (known outcomes in areas with similar HBV endemicity). As HDV is known to increase the severity of acute and chronic hepatitis B 3, the impact of HDV was taken into consideration for those regions where the virus was found to be prevalent.

0.5( i

1 Prevalence of hepatitis B infection in South America based on HBsAg prevalence rates: i-I, <1.3; II, 1.3-3.9; [ ] • I , >4.0

Epidemiology of HBV in Latin America As estimated from data provided by blood banks, HBsAg prevalence varies from low (0.3%) to very high (> 10%) within the region (Figures 1 and 2). In South America, the rate of HBsAg carriage increases from south to north. Very high prevalence rates (5-20%) have been observed in the central and western Amazon region of Brazil and in certain adjacent regions of Colombia, Peru and Venezuela. In Central America, HBV prevalence is low or moderate (1.0-3.0%) as it is in the Caribbean (1.0-2.0%), except for Hispaniola (Dominican Republic and Haiti) where there is a high prevalence 4'5. Table I shows the estimated number of HBV carriers according to region and country based upon blood bank data 6. The total number of carriers in Latin America approaches 6 million, with the entire area of the Amazon basin including parts of Colombia, Venezuela and Peru representing a true reservoir of high endemicity. Out of the estimated four million carriers in South America, > 30% are located in the above-mentioned area, which also includes the northeastern part of Brazil TM. Morbidity estimates for the region (Table 2) indicate that 141000 acute hepatitis B cases will occur in Latin America per year, two thirds of them in South America (76 000 acute cases/year in Brazil and 10 000 in Argentina). In Mexico and Central America, 14000 cases can be expected, while in the Caribbean, 24000 inhabitants would be afflicted. Few data on HBV prevalence by age, race, urban versus rural status, or socioeconomic level is available for any country; in South America, only Argentina and Brazil have consistently reported such data 19'2°. Nevertheless, there are strong indications that disease prevalence may vary according to each of these factors. Data from Brazil and Venezuela 2 ~ suggest higher prevalence rates in lower socioeconomic classes living in large cities 14'15. Studies in Colombia point to increased prevalence in smaller towns and rural areas t3. Both Brazil and Trinidad have reported that HBV occurs more frequently in blacks or persons of mixed race, while studies in Surinam indicate that persons of Indonesian origin may be at higher risk 17'22'23. Indigenous populations in Brazil 24'25, Colombia z6, Panama 27 and Venezuela 2s'29 show very

United States 0.3

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Mexico .?×,co , .u

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GuUl,,f; °f Mexico

r, ~

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Dominican .... Kepuo,c

~_~ J ;.. . 1.6 ~ ¢ ~ Puerto Rico g~,Barbados "~"jlt'Honduras " ~ - H a i t 2.7 0.2 "6 ~'1 u, ~ l / 3.0 o -- " ~ "~ / ~'" ~ Grenada~o ~ ~ Caribbean ~ea 2.1 JTrinidad Guatemala"~,~//-f//r'~ _. ~-~i~ 1 q 2.2 ~r~'~ ~ -~Nicaragua j.r~__~jt~,~._~..~J - - - ~ • El Salvador 1 . 2~...~ [ 1.1 f r . ....... (

Panama 1.0

Figure2 Prevalence of hepatitis B infection in Central America, Mexico, and the Caribbean based on HBsAg prevalence rates: I-I, < 1.3; IB, 1.3-1.9;, • . >4.0

Vaccine, Vol. 8, S u p p l e m e n t 1990

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HBV eradication strategy in Latin America: O.H. Fay et al. Table 1 Prevalence of HBV markers in adult blood donors Rate

Countw

HBsAg + ve (range)

All markers

(%)

(%)

Central America and Mexico Costa Rica 0,6 El Salvador

Guatemala Honduras Mexico Nicaragua Panama

1,2 2.2 (1.4-3) 3 1 (0.33-1.6) 1,1 1 (0.7-1.4)

20.6 16.8 -

Subtotal

10 - 3 x

Estimated HBV carriers

12.7 52.2 145.6 103.2 659.4 26,4 18.3 1027.8

Caribbean Bahamas Barbados Cuba

Dominican R. Grenada Haiti Jamaica Puerto Rico Trinidad

13.1 82.8 61 11.1 -

3.2 3.7 77.8 209.9 2.0 130,4 3.4 6.7 15.8 452.9

Peru

Surinam Uruguay Venezuela Subtotal

1.1 (0.7-2.1) 1.6

16.6 -

290.3 84.6

t

(0.2-1.8) 1 (0.7-1.1) 2 (1,2-2.8) 2.5 (1.2-3.9) 8 (5-13) 0.5 (0.4-0,6) 2.8 (1-4.7) 2

34 6.7 29.3 35.3

0.9

-

1,4 (0.5-3.5) 2.3 0.9 2 (1.3-2.8)

27.3 41 18

187.7 75.5 1034.5 890.5 411.2 54.3 333.5 156.2 26.0 235.5 8.6 2.6 262,4

Total

4053.4

5534.1

high disease rates. Data from the western part of the Amazon basin (Table 3) is especially noteworthy 3°-3". In the state of Amazonas, "/0% of the population under 20 years of age is positive for anti-HBs. In the area of Sao Paulo, when comparing families of occidental and oriental origins, the index cases of HBsAg-positive chronic liver disease show that while both groups generally have an elevated rate of infection, this rate is significantly higher in the oriental group (81.8%) than in the occidental one (36.5%). The chronic carrier rate displays a similar pattern: 4"/.9% in oriental and 10."/% in occidental families. In both ethnic groups, transmission occurs more frequently from mothers than from fathers to their children 38. The northern areas of Chile and Argentina may show higher prevalence rates than the central and southern regions of these countries 36,37. Studies of HBV markers in health care workers have shown conflicting results: while health care workers in Brazil and Argentina (Figure 3) show a 1.5 to twofold higher risk for HBV infection than does the general population, both groups run similar risks in Peru and Chile. In general, however, health care workers through-

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T~Db 2

EstlmatKl annual HBV caes in Latin America

Estimated cases per year 1,4 1,4 0.8 4,1 2.1 2.7 (1.4-4) 1.6 0.2 1.4

Subtotal South America Argentina Bolivia Brazil South Central West Southeast Northeast North Chile Colombia Ecuador Paraguay

out the region have a moderately elevated risk of HBV infection 11'38-41. In contrast, haemodialysis patients "2, drug addicts "3, homosexuals "z~s and mentally retarded children 18 all appear to be at very high risk of disease, especially in urban population centres. In addition, prostitutes"e''7 and diabetics" may be at greater risk when compared with the general population. The sequelae of hepatitis B infection - acute hepatitis, chronic active hepatitis (CAH), cirrhosis, and PHC - have been evaluated by measuring the proportion of cases of each disease that arc due to HBV. In several countircs, HBV

V a c c i n e , Vol. 8, S u p p l e m e n t 1990

Country

Acute

Central American Mexico Costa Rica El Salvador Guatemala

Clinlcal

Fulminant

1650 265O 1100 2250 4300 1200 700

45O 675 575 575 1075 300 175

4-6 6-9 3-5 5-8 10-15 3-5 2-4

Subtotal

13 850

3525

33-52

Caribbean Bahamas Barbados Cuba Dominican R. Grenada Haiti Jamaica Puerto Rico Trinidad

500 50 16500 5000 70 250 65 750 150

125 12 4125 1500 20 65 18 150 35

t-2 0-1 40-60 15-25 0-2 0-3 0-2 2-4 0-3

Subtotal

24335

6080

58-102

9600 410 5750

2400 100 1450

23-33 1-3 16-25

5650 2300 33 700 23 200 10 500 650

1300 575 8500 5800 2925 165

16-25 6-10 84-110 58-75 102-120 2-4

Honduras

Mexico Nicaragua Panama

South America Argentina Bolivia Colombia Brazil

South Central Wast Southeast Northeast North Chile Ecuador Surinam Paraguay

400

100

Uruguay Venezuela Subtotal

550 550 4700 1600 2700

140 140 1175 400 675

102 260

25 545

336-446

Total

140 445

35 150

427-600

Peru

TaMe 3

Age (years)

1-3 1-3 1-3 13-18 5-8 8-12

Age diltrU~timl of mltI-HB8 in the Amazona Slate, Brazil No. studied

0-4 5-9 10-14 15-19 20-24 25-29 30-39 40

528 229 208 47 38 39 78 68

Total

1233

No. anti-HBs positive (%) 59 90 107 33 25 32 87 58

(11.2) (39.3)

(51.4) (70.2) (65.8) (82.0) (85.9) (85.3)

471 (38.2)

HBV eradication strategy in Latin America: O H Fay et al.

21.5

17 T,

II .3

11

#.

10.5 1

0-30

> 50

40-45 15

1.3

Age (years) > 20 Time in the area of work (years)

Figure 3 Comparison of hepatitis B serological markers in Argentine health care workers (r-I) as compared with marker levels in the general population ( I I )

infection accounts for only 1-16% of acute viral hepatitis in children4S'49; however, in high HBV endemicity areas, HBV infection leads to half of the acute hepatitis cases in this age group 5°. In adults, HBV infection accounts for a high proportion (25-67%) of disease in all areas studied, except in Chile 4. Based on the number of cases per year of acute hepatitis B (Table 2), 35 000 annual cases of acute hepatitis B in the region would be icteric. Twenty percent of these (7000) would require hospitalization: 7 days in 25% of cases, 2 weeks in another 25%, and 4 weeks in 50% due to severe disease. Cases of fulminant viral hepatitis caused by HBV in Latin America may vary between 500 and 700 annually. Based on this table, each country can estimate the cost of disease in terms of medical care for clinical acute hepatitis B. National and regional estimates for the yearly number of cases of CAH, cirrhosis, PHC and for mortality due to HBV infection are given in Table 4. If the annual number of CAH cases is estimated as 3% of the acute hepatitis B disease load:, 4100 CAH cases per year would occur in Latin America. The total number of cirrhosis cases in Latin America could range between 18 000 and 61000, accounting for 4500-16 000 deaths per year. These data are in accordance with preliminary results provided by Gayotto and Strauss 49 in their 1987/88 survey. Finally, 15(K)-4000 PHC cases can be expected annually in the region. Coinfection

with

HDV

An unusual type of fulminant hepatitis, characterized by severe hepatitis resulting in encephalopathy or other signs of hepatic failure, has been documented as occurring in two areas of South America - the Santa Marta region of Colombia and the Amazon basin. Described for over 40 years, these distinct entities are known as Santa Marta hepatitis and Labrea hepatitis, respectively 51-5'~. In parallel, reported mortality rates due to acute viral hepatitis in the Amazon basin are the highest in the region. An especially severe hepatitis epidemic broke out during 1979-81 among the Yucpa Indians in western Venezuela 29'55. Recent studies have documented that both disease entities occur in areas of high HBV endemicity where 5-15% of the population are HBsAg carriers, and where HBV infection frequently occurs during childhood. Studies in Venezuela have shown the outbreak to be due to HDV infection of hepatitis B carriers. Other investigations have shown HDV infection

to be highly endemic in the Santa Marta region and in the Amazon basin, and data are now being compiled which strongly suggest that HDV infection of HBV carriers is partially or fully responsible for the occurrence of both Santa Marta and Labrea hepatitis 56-59. The endemicity of &infection varies widely throughout the region. In areas of low to moderate HBV endemicity, 6 infection shows modest prevalence rates. Studies of asymptomatic HBV carriers in Chile were negative for &6o, while in Rio de Janeiro, only one &-positive person was' found among 200 HBV carriers 61. Furthermore, studies of HBsAg-positive CAH cases in Argentina have shown 5% positive levels for & antibody, while & was found in 1.5% of 1100 HBsAg-positive blood donors 6:. By contrast, studies in high HBV endemicity regions show very high prevalence of 6 infection. Investigations in the Amazon basin have identified the presence of HDV in at least 15 cities and villages including Manaus aS. HDV positivity is found in 20--30% of HBV carriers and acute hepatitis cases, in 85-90% of CAH and cirrhosis cases, and in 30-50% of fulminant hepatitis B cases in this region a2'6a. Surveys in Venezuela indiate that &virus continues to spread among the Yucpa Indians who are HBV carriers: 5-10% of susceptible HBV carriers become infected yearly and up to 50% develop CAH 64. Infection with delta virus is also widespread in the Santa Marta region of Colombia, occurring with the greatest frequency in villages with fulminant Santa Marta hepatitis 51. At the 1988 PAHO-sponsored meeting of the Advisory Group on Viral Hepatitis, it was reported that sporadic

Table 4 Estimated annual sequelae of HVB infection and deaths in Latin America Disease sequelae Country

CAH

Central America and Mexico Costa Rica 48 El Salvador 77 Guatemala 32 Honduras 65 Mexico 124 Nicaragua 35 Panama 20

Cirrhosis

Death

PHC

206-721 331-1158 138-483 281-g84 537-1880 150-525 88-308

53-185 85-298 351-122 72-252 138-483 38-133 22-77

17-47 26-71 11-30 23-63 43-118 12-33 7-20

Subtotal

401

1731-6059

443-1550

139-382

Caribbean Bahamas Barbados Cuba Dominican R. Grenada Haiti Jamaica Puerto Rico Trinidad Subtotal

14 2 478 174 2 7 2 22 5 706

63- 220 6- 21 2062-7217 750-2625 9- 32 31-108 8- 28 94- 329 19-67 3042-10647

15-56 2-7 528-1848 192-672 2-7 8-28 2-7 24-84 5-17 779-2726

5-14 1-3 165-453 60-165 1-3 2-5 1-3 7-19 2-5 244-670

South America Argentina Bolivia Colombia Brazil Chile Ecuador Paraguay Peru Surinam Uruguay Venezuela

278 12 167 2185 1920 12 16 136 16 46 78

1200-4200 51-178 719-2517 9419-32965 81-284 50-175 69-241 587- 2055 69-241 200-700 337-1180

307-1074 13-46 184-644 244-8438 26-70 13-46 18-63 150-525 18-63 51-179 86-301

96-264 4-11 57-157 754-2073 7-19 4-11 5-14 47-129 5-14 16-44 27-74

Subtotal

2965

12782-44737

3271-11449

1022-2810

Total

4072

17 555-61443

4493-15725

1405-3862

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HBV eradication strategy in Latin America. O.H. Fay et al.

epidemic outbursts of fulminant hepatitis with high mortality rates (30-36%) occur in the Andes region of Avaucay, Peru, where 10% of the population is anti_HDV.positive 65.~,~.

Transmission of HBV While HBV infection and H BV-assoclated diseases are prevalent in Latin America, large regional differences exist in infection and carrier rates within this area; HBV carrier prevalence may also vary greatly within individual countries. In terms of regional morbidity and mortality, this produces a true mosaic of pathologies. Within certain Latin American countries, disease endemicity varies widely, depending on racial, socioeconomic, geographical and other factors. Variations observed in Peru and Brazil are particularly striking, with prevalence rates ranging from low to very high in 'large segments of the population. Immigration and migration of populations can also give rise to rapid changes in epidemiological patterns. For instance, the oriental community in southern Brazil is growing at a fast pace; in this group the rate of infection is three times higher than that in occidental inhabitants 3~ Relatively few studies of HBV transmission have been completed in the region. Presumably transmission occurs by the same routes described in other parts of the world, i.e. by percutaneous or permucosal exposure to infected blood or other secretions, in adults, the predominant means of transmission are likely to be needlestick accidents (in the hospital or among drug users) or blood transfusion. Indeed, the important increase in drug addiction occurring in many of tile larger cities of Mexico. Argentina, Brazil and Colombia, is a source of disease transmission that must be increasingly considered. Some studies have revealed HBsAg positivily rates of 18% with overall marker rates for infection ~anti-HBs and antiHBc) of up to 85% among intravenous drug users. The association of HBV and HDV is extremely important in this group since HDV intection among drug addicts in Argentina increased four- to sixfold in the last 3 years°" Illicit donation of HBV- and HDV-contaminated blood by addicts as well as by volunteer donors paid under cover constitutes a serious dissemination factor for both viruses. Undoubtedly, perinatal transmission plays an important role in those areas where HBV transmission is apparent during childhood. Studies of transmission 5°5 in Manaus, Brazil are especially revealing. In this Amazonian city, most cases of acute HBV occur during the first years of life: anti-HBV antibodies (anti-HBs and anti-HBc) increase at a similar rate in the population as do those of antibodies to hepatiti~ A virus. As vertical transmission cannot be regarded as the sole source of endemicity in the area, other environmental, socioeconomic and sanitary factors must be considered. The incidence of reported hepatitis B cases in rural areas of the State of Amazon has been higher than those in urban centres in the past few years ~° Acute and chronic liver disease, the consequences of HBV infection, are related to the age at which infection occurs. In Brazil, symptomatic acute hepatitis is an uncommon entity in infected younger children, but occurs in ~ 33% of infected older children and adults 68. Conversely, persistent viral infection occurs in only 5-10% of infected older children and adults but develops

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Vaccine, Vol. 8, Supplement 1990

in almost 20% of 1.5-year-old infected children and in 90% of newborns to HBV carrier mothers. The risks of cirrhosis or liver cancer in persons with persistent intbction are also related to the age of infection, with PHC being more likely to develop in those infected at a younger age 69. However, available data do not suggest that disease outcomes vary by race or country of origin. Thus, in areas of higher HBV endemicity, the consequences of infection during childhood are not expected to be different from country to country. Basic estimates of disease outcome from one country can therefore be used with reasonable reliability in another. Population studies concerning the incidence of PHC show rates to be similar to those in the US and Europe~ but lower than those in Southeast Asia and sub-Saharan Africa v°, In one Brazilian survey, only 31% of PHC patients were shown to be HBsAg-positive 3~ Oriental carriers have been shown t~ be more prone to develop PHC than non-oriental carriers. It is expected that future investigations in high-endemicity areas such as the Amazon basin will shed more light on the relationship between HBV and PHC in the region.

Controlling hepatitis in the Latin American region While HBV seroprevalence studies in the region should be stimulated, improved and integrated within national programmes, sufficient data is presently available to formulate clear and precise strategies leading to the prevention, control and even eradication of HBV in Latin America. Urgent action is needed since the urban population centres in this region are the fastest growing in the world: at the same time, certain areas have endemicity rates that are also among the highest in the world. Hence, HBV immunization programmes must be aimed at controlling the expanding viral reservoirs in such regions. In areas of high HBV endemicity ( > 5% HBV carriers), the prevention of perinatal and early childhood HBV transmission by massive vaccination of infants and children has been advocated ~ particularly in the worst-affected rural areas. Due to the severe potential chronic sequelae which may develop in children born to HBV carrier mothers, prevention of perinatal HBV is of utmost importance. In low endemicity areas ( < 1% HBV carriers), the use of the hepatitis B vaccine is particularly advisable in high-risk adult populations (health c~re workers, homosexuals, drug addicts, etc~). Such vaccination programmes should be complemented, supported and monitored by a series of measures where appropriate including: a system of vaccine delivery to immunize children, based on the chosen vaccination protocol; a Board composed of national medical authorities to assure the appropriate use, and quality control, of vaccines; national reference laboratories to assess immune response and persistence of antibodies in vaccinated populations; and a national system of disease surveillance to monitor the incidence of acute hepatitis B and the development of chronic disease (i.e., chronic active hepatitis, cirrhosis, liver cancer). These measures should also be supplemented by informational, educational and motivational activities focussed on the general population, but targeted to medical and paramedical staff. In summary, there is a pressing need to initiate various types of HBV immunization programmes geared towards

HBV eradication strategy in Latin America: O.H. Fay et al.

the needs of individual Latin American countries. The creation and implementation of such programmes necessarily presents challenges to Latin American countries, many of them burdened by huge foreign debts, as well as pressing social, educational and public health problems. Thus, considerations of cost-effectiveness will be of paramount importance. The Latin American Regional Study Group recommends that Latin American health authorities initiate policies that will result in the eradication of HBV from this region. Hopefully, technical and economic support from international institutions and organizations can be combined with efforts by Latin American organizations and individual countries to mount effective, long-term vaccination programmes to achieve the goal of HBV eradication. Acknowledgements The Latin American Regional Study Group extends its gratitude to Dr S. Hadler (CDC, Atlanta, GA) for his kind cooperation concerning this report. The Committee Chairman wishes to thank Betty Galiano for her editorial assistance and his secretaries, Sara Lopez Dupuy and Laura Ghidara for their valuable help.

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